The use of small agonists to target stimulators of interferon genes (STING) has been demonstrated to be a promising strategy for the treatment of various cancers and infectious diseases. Herein, we discovered a series of 1H-pyrrole-3-carbonitrile derivatives as potential STING agonists. On this basis, the structure–activity relationship of this scaffold was studied by introducing various substituents on the aniline ring system. Representative compounds 7F, 7P, and 7R all displayed comparable activities to the reported STING agonist SR-717 in binding various hSTING alleles and induced reporter signal in human THP1 cell lines. Model compound 7F induced phosphorylation of TBK1, IRF3, p65, and STAT3 in a STING-dependent fashion and stimulated the expression of target genes IFNB1, CXCL10, and IL6 in a time-dependent manner in human THP1 cells. Our findings afforded a series of novel STING agonists with promising potential.

中文翻译：

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1H-吡咯-3-甲腈衍生物作为 STING 受体激动剂的构效关系研究

使用小激动剂靶向干扰素基因刺激物（STING）已被证明是治疗各种癌症和传染病的一种有前途的策略。在此，我们发现了一系列 1 H-吡咯-3-甲腈衍生物作为潜在的 STING 激动剂。在此基础上，通过在苯胺环体系上引入各种取代基，研究了该支架的构效关系。代表性化合物7F、7P和7R在结合各种 hSTING 等位基因并在人 THP1 细胞系中诱导报告信号方面均表现出与报道的 STING 激动剂 SR-717 相当的活性。在人THP1细胞中，模型化合物7F以STING依赖性方式诱导TBK1、IRF3、p65和STAT3的磷酸化，并以时间依赖性方式刺激靶基因IFNB1、CXCL10和IL6的表达。我们的研究结果提供了一系列具有良好潜力的新型 STING 激动剂。